tbuckley/cabot-search huggingface dataset:
Pulmonary inflammation and fibroblast immunoregulation: from bench to bedside
Authors: Mohamed A Ghonim, David F Boyd, Tim Flerlage, Paul G Thomas
Journal: Journal of Clinical Investigation (2023)

In recent years, there has been an explosion of interest in how fibroblasts initiate, sustain, and resolve inflammation across disease states. Fibroblasts contain heterogeneous subsets with diverse functionality. The phenotypes of these populations vary depending on their spatial distribution within the tissue and the immunopathologic cues contributing to disease progression. In addition to their roles in structurally supporting organs and remodeling tissue, fibroblasts mediate critical interactions with diverse immune cells. These interactions have important implications for defining mechanisms of disease and identifying potential therapeutic targets. Fibroblasts in the respiratory tract, in particular, determine the severity and outcome of numerous acute and chronic lung diseases, including asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, and idiopathic pulmonary fibrosis. Here, we review recent studies defining the spatiotemporal identity of the lung-derived fibroblasts and the mechanisms by which these subsets regulate immune responses to insult exposures and highlight past, current, and future therapeutic targets with relevance to fibroblast biology in the context of acute and chronic human respiratory diseases. This perspective highlights the importance of tissue context in defining fibroblast-immune crosstalk and paves the way for identifying therapeutic approaches to benefit patients with acute and chronic pulmonary disorders.
The chronicles of hepatocellular carcinoma classification: Subtyping, modeling, and treatment
Authors: Shu Shimada, Shinji Tanaka
Journal: Hepatology (2023)

Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan Abbreviations: FAD, fatty acid degradation; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty acid disease; NASH, non-alcoholic steatohepatitis; TCGA, the Cancer Genome Atlas Research Network. Correspondence Shinji Tanaka, Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Email: [email protected]
Immune checkpoint blockade induces distinct alterations in the microenvironments of primary and metastatic brain tumors
Authors: Lu Sun, Jenny C. Kienzler, Jeremy G. Reynoso, Alexander Lee, Eileen Shiuan, Shanpeng Li, Jiyoon Kim, Lizhong Ding, Amber J. Monteleone, Geoffrey C. Owens, Joanna J. Phillips, Richard G. Everson, David Nathanson, Timothy F. Cloughesy, Gang Li, Linda M. Liau, Willy Hugo, Won Kim, Robert M. Prins
Journal: Journal of Clinical Investigation (2023)

In comparison with responses in recurrent glioblastoma (rGBM), the intracranial response of brain metastases (BrM) to immune checkpoint blockade (ICB) is less well studied. Here, we present an integrated single-cell RNA-Seq (scRNA-Seq) study of 19 ICB-naive and 9 ICB-treated BrM samples from our own and published data sets. We compared them with our previously published scRNA-Seq data from rGBM and found that ICB led to more prominent T cell infiltration into BrM than rGBM. These BrM-infiltrating T cells exhibited a tumor-specific phenotype and displayed greater activated/exhausted features. We also used multiplex immunofluorescence and spatial transcriptomics to reveal that ICB reduced a distinct CD206+ macrophage population in the perivascular space, which may modulate T cell entry into BrM. Furthermore, we identified a subset of progenitor exhausted T cells that correlated with longer overall survival in BrM patients. Our study provides a comprehensive immune cellular landscape of ICB's effect on metastatic brain tumors and offers insights into potential strategies for improving ICB efficacy for brain tumor patients.
The emerging importance of lymphatics in health and disease: an NIH workshop report
Authors: Babak J. Mehrara, Andrea J. Radtke, Gwendalyn J. Randolph, Brianna T. Wachter, Patricia Greenwel, Ilsa I. Rovira, Zorina S. Galis, Selen C. Muratoglu
Journal: Journal of Clinical Investigation (2023)

The lymphatic system (LS) is composed of lymphoid organs and a network of vessels that transport interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials in the body. Abnormal development or malfunction of the LS has been shown to play a key role in the pathophysiology of many disease states. Thus, improved understanding of the anatomical and molecular characteristics of the LS may provide approaches for disease prevention or treatment. Recent advances harnessing single-cell technologies, clinical imaging, discovery of biomarkers, and computational tools have led to the development of strategies to study the LS. This Review summarizes the outcomes of the NIH workshop entitled "Yet to be Charted: Lymphatic System in Health and Disease," held in September 2022, with emphasis on major areas for advancement. International experts showcased the current state of knowledge regarding the LS and highlighted remaining challenges and opportunities to advance the field.
SAP30 promotes breast tumor progression by bridging the transcriptional corepressor SIN3 complex and MLL1
Authors: Lei Bao, Ashwani Kumar, Ming Zhu, Yan Peng, Chao Xing, Jennifer E Wang, Yingfei Wang, Weibo Luo
Journal: Journal of Clinical Investigation (2023)

SAP30 is a core subunit of the transcriptional corepressor SIN3 complex, but little is known about its role in gene regulation and human cancer. Here, we show that SAP30 was a nonmutational oncoprotein upregulated in more than 50% of human breast tumors and correlated with unfavorable outcomes in patients with breast cancer. In various breast cancer mouse models, we found that SAP30 promoted tumor growth and metastasis through its interaction with SIN3A/3B. Surprisingly, the canonical gene silencing role was not essential for SAP30's tumor-promoting actions. SAP30 enhanced chromatin accessibility and RNA polymerase II occupancy at promoters in breast cancer cells, acting as a coactivator for genes involved in cell motility, angiogenesis, and lymphangiogenesis, thereby driving tumor progression. Notably, SAP30 formed a homodimer with 1 subunit binding to SIN3A and another subunit recruiting MLL1 through specific Phe186/200 residues within its transactivation domain. MLL1 was required for SAP30-mediated transcriptional coactivation and breast tumor progression. Collectively, our findings reveal that SAP30 represents a transcriptional dependency in breast cancer.
Elevated periprostatic venous testosterone correlates with prostate cancer progression after radical prostatectomy
Authors: Mohammad Alyamani, Patrick Michael, Daniel Hettel, Lewis Thomas, Scott D Lundy, Mike Berk, Mona Patel, Jianbo Li, Hooman Rashidi, Jesse K McKenney, Eric A Klein, Nima Sharifi
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDGenerally, clinical assessment of gonadal testosterone (T) in human physiology is determined using concentrations measured in peripheral blood. Prostatic T exposure is similarly thought to be determined from peripheral T exposure. Despite the fact that androgens drive prostate cancer, peripheral T has had no role in the clinical evaluation or treatment of men with localized prostate cancer.METHODSTo assess the role of local androgen delivery in prostate cancer, we obtained blood from the (periprostatic) prostatic dorsal venous complex in 266 men undergoing radical prostatectomy from July 2014 to August 2021 and compared dorsal T (DT) levels with those in circulating peripheral blood (PT) and prostatic tissue. Comprehensive targeted steroid analysis and unbiased metabolomics analyses were performed. The association between the DT/PT ratio and progression-free survival after prostatectomy was assessed.RESULTSSurprisingly, in some men, DT levels were enriched several-fold compared with PT levels. For example, 20% of men had local T concentrations that were at least 2-fold higher than peripheral T concentrations. Isocaproic acid, a byproduct of androgen biosynthesis, and 17-OH-progesterone, a marker of intratesticular T, were also enriched in the dorsal vein of these men, consistent with testicular shunting. Men with enriched DT had higher rates of prostate cancer recurrence. DT/PT concentration ratios predicted worse outcomes even when accounting for known clinical predictors.CONCLUSIONSThese data suggest that a large proportion of men have a previously unappreciated exposure to an undiluted and highly concentrated T supply. Elevated periprostatic T exposure was associated with worse clinical outcomes after radical prostatectomy.FUNDINGNational Cancer Institute (NCI), NIH grants R01CA172382, R01CA236780, R01CA261995, R01CA249279, and R50CA251961; US Army Medical Research and Development Command grants W81XWH2010137 and W81XWH-22-1-0082.
Hypoxic erythrocytes mediate cardioprotection through activation of soluble guanylate cyclase and release of cyclic GMP
Authors: Jiangning Yang, Michaela L. Sundqvist, Xiaowei Zheng, Tong Jiao, Aida Collado, Yahor Tratsiakovich, Ali Mahdi, John Tengbom, Evanthia Mergia, Sergiu-Bogdan Catrina, Zhichao Zhou, Mattias Carlström, Takaaki Akaike, Miriam M. Cortese-Krott, Eddie Weitzberg, Jon O. Lundberg, John Pernow
Journal: Journal of Clinical Investigation (2023)

Red blood cells (RBCs) mediate cardioprotection via nitric oxide-like bioactivity, but the signaling and the identity of any mediator released by the RBCs remains unknown. We investigated whether RBCs exposed to hypoxia release a cardioprotective mediator and explored the nature of this mediator. Perfusion of isolated hearts subjected to ischemia-reperfusion with extracellular supernatant from mouse RBCs exposed to hypoxia resulted in improved postischemic cardiac function and reduced infarct size. Hypoxia increased extracellular export of cyclic guanosine monophosphate (cGMP) from mouse RBCs, and exogenous cGMP mimicked the cardioprotection induced by the supernatant. The protection induced by hypoxic RBCs was dependent on RBC-soluble guanylate cyclase and cGMP transport and was sensitive to phosphodiesterase 5 and activated cardiomyocyte protein kinase G. Oral administration of nitrate to mice to increase nitric oxide bioactivity further enhanced the cardioprotective effect of hypoxic RBCs. In a placebo-controlled clinical trial, a clear cardioprotective, soluble guanylate cyclase-dependent effect was induced by RBCs collected from patients randomized to 5 weeks nitrate-rich diet. It is concluded that RBCs generate and export cGMP as a response to hypoxia, mediating cardioprotection via a paracrine effect. This effect can be further augmented by a simple dietary intervention, suggesting preventive and therapeutic opportunities in ischemic heart disease.
Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression
Authors: Joseph S Dolina, Joey Lee, Spencer E Brightman, Sara McArdle, Samantha M Hall, Rukman R Thota, Karla S Zavala, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Jason A Greenbaum, Ezra E W Cohen, Bjoern Peters, Stephen P Schoenberger
Journal: Journal of Clinical Investigation (2023)

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response to ICB of an aggressive low-TMB squamous cell tumor could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. We believe that the concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.
Meet the First Authors
Authors: Jakub Tomek Is A Sir
Journal: Circulation Research (2023)

He combines advanced computational modelling, cell and whole-heart imaging and image analysis to understand the mechanisms of cardiac arrhythmia and disease remodeling, currently focusing on diabetes.When not 'sciencing' or parenting, he enjoys playing music on the uilleann pipes and drinking tea (especially sheng puerh).He aims to spread the correct/original pronunciation of J. E. Purkinje ("Purkinye", not "Purkinzhee") across the world.He can be found on Twitter @JakubTomek13.
Autotaxin suppresses cytotoxic T cells via LPAR5 to promote anti–PD-1 resistance in non–small cell lung cancer
Authors: Jessica M Konen, B Leticia Rodriguez, Haoyi Wu, Jared J Fradette, Laura Gibson, Lixia Diao, Jing Wang, Stephanie Schmidt, Ignacio I Wistuba, Jianjun Zhang, Don L Gibbons
Journal: Journal of Clinical Investigation (2023)

Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and effector tumor-infiltrating CD8+ T cells. Pharmacological inhibition of ATX, or the downstream receptor LPAR5, in combination with anti-PD-1 was sufficient to restore the antitumor immune response and efficaciously control lung tumor growth in multiple KP tumor models. Additionally, ATX was significantly correlated with inflammatory gene signatures, including a CD8+ cytolytic score in multiple lung adenocarcinoma patient data sets, suggesting that an activated tumor-immune microenvironment upregulates ATX and thus provides an opportunity for cotargeting to prevent acquired resistance to anti-PD-1 treatment. These data reveal the ATX/LPA axis as an immunosuppressive pathway that diminishes the immune checkpoint blockade response in lung cancer.
Epitope base editing CD45 in hematopoietic cells enables universal blood cancer immune therapy
Authors: Nils Wellhausen, Ryan P. O’Connell, Stefanie Lesch, Nils W. Engel, Austin K. Rennels, Donna Gonzales, Friederike Herbst, Regina M. Young, K. Christopher Garcia, David Weiner, Carl H. June, Saar I. Gill
Journal: Science Translational Medicine (2023)

In the absence of cell surface cancer-specific antigens, immunotherapies such as chimeric antigen receptor (CAR) T cells, monoclonal antibodies, or bispecific T cell engagers typically target lineage antigens. Currently, such immunotherapies are individually designed and tested for each disease. This approach is inefficient and limited to a few lineage antigens for which the on-target/off-tumor toxicities are clinically tolerated. Here, we sought to develop a universal CAR T cell therapy for blood cancers directed against the pan-leukocyte marker CD45. To protect healthy hematopoietic cells, including CAR T cells, from CD45-directed on-target/off-tumor toxicity while preserving the essential functions of CD45, we mapped the epitope on CD45 that is targeted by the CAR and used CRISPR adenine base editing to install a function-preserving mutation sufficient to evade CAR T cell recognition. Epitope-edited CD45 CAR T cells were fratricide resistant and effective against patient-derived acute myeloid leukemia, B cell lymphoma, and acute T cell leukemia. Epitope-edited hematopoietic stem cells (HSCs) were protected from CAR T cells and, unlike CD45 knockout cells, could engraft, persist, and differentiate in vivo. Ex vivo epitope editing in HSCs and T cells enables the safe and effective use of CD45-directed CAR T cells and bispecific T cell engagers for the universal treatment of hematologic malignancies and might be exploited for other diseases requiring intensive hematopoietic ablation.
Prominent in vivo influence of single interneurons in the developing barrel cortex
Authors: Yannick Bollmann, Laura Modol, Thomas Tressard, Artem Vorobyev, Robin Dard, Sophie Brustlein, Ruth Sims, Imane Bendifallah, Erwan Leprince, Vincent de Sars, Emiliano Ronzitti, Agnès Baude, Hillel Adesnik, Michel Aimé Picardo, Jean-Claude Platel, Valentina Emiliani, David Angulo-Garcia, Rosa Cossart
Journal: Nature Neuroscience (2023)
Reducing the risks of nuclear war: the role of health professionals
Authors: Kamran Abbasi, Parveen Ali, Virginia Barbour, Kirsten Bibbins-Domingo, Marcel G M Olde Rikkert, Peng Gong, Andy Haines, Ira Helfand, Richard Horton, Bob Mash, Arun Mitra, Carlos Monteiro, Elena N Naumova, Eric J Rubin, Tilman Ruff, Peush Sahni, James Tumwine, Paul Yonga, Chris Zielinski
Journal: Cardiovascular Research (2023)
Endoscopic ultrasound-guided reintervention for biliary metal stent kinking using a device delivery system
Authors: Kei Yane, Masahiro Yoshida, Kota Hanada, Kotaro Morita, Hideyuki Ihara, Tetsuya Sumiyoshi, Hitoshi Kondo
Journal: Endoscopy (2023)

Kinking of the stent is one of the major causes of biliary metal stent dysfunction [1]. Although the preferred treatment is to remove the stent and deploy a new one, this is difficult to do in patients with duodenal obstruction due to tumor invasion. Herein, we report a case of successful endoscopic ultrasound (EUS)-guided reintervention for biliary metal stent kinking using a device delivery system.
Bacteraemia with gram-positive bacteria—when and how do I need to look for endocarditis?
Authors: Magnus Rasmussen, Patrik Gilje, Erika Fagman, Andreas Berge
Journal: Clinical Microbiology and Infection (2023)

BackgroundPatients with bacteraemia caused by gram-positive bacteria are at risk for infective endocarditis (IE). Because IE needs long antibiotic treatment and sometimes heart valve surgery, it is very important to identify patients with IE.ObjectivesIn this narrative review we present and discuss how to determine which investigations to detect IE that are needed in individual patients with gram-positive bacteraemia.SourcesPublished original studies and previous reviews in English, within the relevant field are used.ContentFirst, the different qualities of the bacteraemia in relation to IE risk are discussed. The risk for IE in bacteraemia is related to the species of the bacterium but also to monomicrobial bacteraemia and the number of positive cultures. Second, patient-related factors for IE risk in bacteraemia are presented. Next, the risk stratification systems to determine the risk for IE in gram-positive bacteraemia caused by Staphylococcus aureus, viridans streptococci, and Enterococcus faecalis are presented and their use is discussed. In the last part of the review, an account for the different modalities of IE-investigations is given. The main focus is on echocardiography, which is the cornerstone of IE-investigations. Furthermore, 18F-fluorodesoxyglucose positron emission tomography/computed tomography and cardiac computed tomography are presented and their use is also discussed. A brief account for investigations used to identify embolic phenomena in IE is also given. Finally, we present a flowchart suggesting which investigations to perform in relation to IE in patients with gram-positive bacteraemia.ImplicationsFor the individual patient as well as the healthcare system, it is important both to diagnose IE and to decide when to stop looking for IE. This review might be helpful in finding that balance.
Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease
Authors: Prabha Chandrasekaran, Yu Han, Christa S. Zerbe, Theo Heller, Suk See DeRavin, Samantha A. Kreuzberg, Beatriz E. Marciano, Yik Siu, Drew R. Jones, Roshini S. Abraham, Michael C. Stephens, Amy M. Tsou, Scott Snapper, Sean Conlan, Poorani Subramanian, Mariam Quinones, Caroline Grou, Virginie Calderon, Clayton Deming, Jennifer W. Leiding, Danielle E. Arnold, Brent R. Logan, Linda M. Griffith, Aleksandra Petrovic, Talal I. Mousallem, Neena Kapoor, Jennifer R. Heimall, Jessie L. Barnum, Malika Kapadia, Nicola Wright, Ahmad Rayes, Sharat Chandra, Larisa A. Broglie, Deepak Chellapandian, Christin L. Deal, Eyal Grunebaum, Stephanie Si Lim, Kanwaldeep Mallhi, Rebecca A. Marsh, Luis Murguia-Favela, Suhag Parikh, Fabien Touzot, Morton J. Cowan, Christopher C. Dvorak, Elie Haddad, Donald B. Kohn, Luigi D. Notarangelo, Sung-Yun Pai, Jennifer M. Puck, Michael A. Pulsipher, Troy R. Torgerson, Elizabeth M. Kang, Harry L. Malech, Julia A. Segre, Clare E. Bryant, Steven M. Holland, Emilia Liana Falcone
Journal: Journal of Allergy and Clinical Immunology (2023)

Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments.
Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression
Authors: Alexandros Papachristodoulou, Isabel Heidegger, Renu K. Virk, Matteo Di Bernardo, Jaime Y. Kim, Caroline Laplaca, Florencia Picech, Georg Schäfer, Guarionex Joel De Castro, Hanina Hibshoosh, Massimo Loda, Helmut Klocker, Mark A. Rubin, Tian Zheng, Mitchell C. Benson, James M. McKiernan, Aditya Dutta, Cory Abate-Shen
Journal: European Urology (2023)
Evaluation of a point-of-care test for the diagnosis of Taenia solium neurocysticercosis in rural southern Tanzania: a diagnostic accuracy study
Authors: Dominik Stelzle, Charles E Makasi, Veronika Schmidt, Inge Van Damme, Chiara Trevisan, Charlotte Ruether, Agnès Fleury, John Noh, Sukwan Handali, Pierre Dorny, Pascal Magnussen, Gideon Zulu, Kabemba E Mwape, Emmanuel Bottieau, Sarah Gabriël, Bernard J Ngowi, Andrea S Winkler, Chishala Chabala, Chishimba Mubanga, Famke Jansen, Isaac K. Phiri, Richard Mambo
Journal: The Lancet Infectious Diseases (2023)
Safety, efficacy, and immunogenicity of a replication-defective human cytomegalovirus vaccine, V160, in cytomegalovirus-seronegative women: a double-blind, randomised, placebo-controlled, phase 2b trial
Authors: Rituparna Das, Daniel Blázquez-Gamero, David I Bernstein, Soren Gantt, Oliver Bautista, Karen Beck, Anthony Conlon, Daniel I S Rosenbloom, Dai Wang, Michael Ritter, Beth Arnold, Paula Annunziato, Kevin L Russell
Journal: The Lancet Infectious Diseases (2023)
Re: Petros Grivas, Se Hoon Park, Eric Voog, et al. Avelumab First-line Maintenance Therapy for Advanced Urothelial Carcinoma: Comprehensive Clinical Subgroup Analyses from the JAVELIN Bladder 100 Phase 3 Trial. Eur Urol 2023;84:95–108
Authors: Yao-Ning Feng, Guang-Yu Xie, Li Xiao
Journal: European Urology (2023)